Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. In some forms of ALS, protein misfolding and aggregation of specific proteins, including Cu/Zn superoxide dismutase (SOD1), have been implicated in motor neuron degeneration. Considerable advances in the understanding of neurodegenerative diseases, including ALS, have been made through studies involving genetically engineered mouse models. However, the complexity, time, and resources required for analyzing age-dependent neurodegeneration in mice limit the usefulness of mouse systems for large-scale genetic and chemical screens. To overcome these limitations, this laboratory has developed and validated a simpler invertebrate model of ALS in Caenorhabditis elegans, a fast- growing, transparent nematode that is amenable to molecular genetic analysis. This C. elegans model recapitulates the major features of human ALS, including a pronounced locomotor defect and the protein aggregation pathology in neurons. This model has made it possible to dissect the mechanism of SOD1-induced neurodegeneration in an efficient manner, using unbiased and large-scale genetic screens. These studies have led to the identification of genes that influence and modulate the neurodegeneration and protein aggregation in ALS disease models. The goal of the proposed project is to identify and elucidate the mechanisms through which ALS pathogenesis is influenced by these novel modifiers. The specific aims are to identify and characterize key genes that influence and modulate the disease, to delineate the pathways through which the pathogenesis is influenced, and to extend the findings to related mammalian systems. The proposed studies, which combine mammalian systems with innovative and promising approaches using C. elegans, are expected to provide insight into fundamental mechanisms of neurodegeneration that may lead to novel approaches for treating ALS and related neurodegenerative diseases.